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A novel mechanism underlying the susceptibility of neuronal cells to nitric oxide: the occurrence and regulation of protein S ‐nitrosylation is the checkpoint
Author(s) -
He J.,
Wang T.,
Wang P.,
Han P.,
Yin Q.,
Chen C.
Publication year - 2007
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2007.04651.x
Subject(s) - nitric oxide , neurotoxicity , s nitrosylation , glutathione , s nitrosoglutathione , microbiology and biotechnology , chemistry , biochemistry , guanosine , biology , cysteine , toxicity , enzyme , endocrinology , organic chemistry
The susceptibility of neuronal cells to nitric oxide (NO) is a key issue in NO‐mediated neurotoxicity. However, the underlying mechanism remains unclear. As a cyclic guanosine monophosphate (cGMP)‐independent NO signaling pathway, S ‐nitrosylation (or S ‐nitrosation) has been suggested to occur as a post‐translational modification in parallel with O‐phosphorylation. The underlying mechanism of the involvement of protein S ‐nitrosylation in the susceptibility of neuronal cells to NO has been little investigated. In this study, we focused on the role of S ‐nitrosothiols (RSNO) in the susceptibility of a cerebellar cell line R2 to NO. Our results showed the following: (i) S ‐nitrosoglutathione (GSNO) induced a burst of RSNO in GSH‐depleted R2 cells, the majority of which were primarily contributed by the S ‐nitrosylation of proteins (Pro‐SNOs), and was followed by severe neuronal necrosis; (ii) the elevation in the level of Pro‐SNOs resulted from a dysfunction of S ‐nitroglutathione reductase (GSNOR) as a result of its substrate, GSNO, being unavailable in GSH‐depleted cells. In the meantime, the suppression of GSNOR increased NO‐mediated neurotoxicity in R2 cells, as well as in cerebellar granule neurons; (iii) Our results also demonstrate that the burst of RSNO is the “checkpoint” of cell fate: if RSNO can be reduced to free thiol proteins, cells will survive; if they are further oxidized, cells will die; and (iv) GSH‐ethyl ester and Vitamin C protected R2 cells against GSNO neurotoxicity through two distinct mechanisms: by inhibiting the elevation of Pro‐SNOs and by reducing Pro‐SNOs to free thiol proteins, respectively. A novel mechanism underlying the susceptibility of neuronal cells to NO is proposed and some potential strategies to prevent the NO‐mediated neurotoxicity are discussed.